Significance Development of a preventive or therapeutic vaccine against HIV is a major priority in the worldwide AIDS epidemic. Due to the many advantages of the system, including safety, there has been special interest in the development of synthetic peptide vaccines against HIV-1. However, the main obstacle to achieve this goal has been the lack of an effective approach to account for epitope glycoprotein variability by immunization Objectives The central question is how to induce an effective immune response to a pathogen containing a protein that is variable at the epitope level. Results We have designed a synthetic peptide approach to reproduce the variation of the hypervariable regions of the HIV-1 envelope glycoprotein. The design and composition of the vaccine is based on an evolutionary homology computer analysis. The final synthetic peptide complex represents the variability of all the major epitopes and induces antibodies with enhanced and broad immunoreactivity to epitope analogs. Five synthetic constructs were designed, synthesized and tested individually and as a complete vaccine preparation. The complete vaccine consists of a complex representing each one of five hypervariable epitopes. Sera from HIV-1 and AIDS positive patients from San Francisco, Canada and Puerto Rico were used to obtain a good representation of antibodies to the epitope sequences circulating in our target population, and to determine if our vaccine represents the hypervariable epitope sequences present in infected humans. We used a large number of patients to document bind ing of HIV-1 specific antibodies to the combined synthetic constructs representing the five hyper variable regions of gp120. This complex immunogen was widely recognized by antibodies contained in pooled and individual sera from HIV-1 positive individuals and AIDS patients. In addition, high titers of HIV-1 antibodies were induced following immunization of mice, rabbits and monkeys with the individual constructs, as well as with the complete vaccine preparation. Future Directions Our design represents proof of concept and should become an important component of vaccines against variable pathogens. Since our results show that antibodies from HIV-1 patient sera bind to the vaccine, and that the complex is highly immunogenic in animals, we conclude that this preparation constitutes a safe and promising AIDS vaccine candidate. KEY WORDS HIV vaccine, glycoprotein, synthetic peptide FUNDING NIH Grant AI35521